title: Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis.
abstract: We previously found that CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) expand in response to Mycobacterium tuberculosis infection in individuals who are healthy tuberculin reactors, but not in tuberculin-negative individuals. We also found that the M. tuberculosis mannose-capped lipoarabinomannan and prostaglandin E2 produced by monocytes are involved in Treg expansion. In this study, we found that Tregs expanded from CD4(+)CCR4(+) cells but not from CCR4(-) cells. However, introduction of CCR4 small interfering RNA (siRNA) into CD4(+) cells only marginally reduced expansion of Tregs. Using siRNA and neutralizing antibodies, we found that expansion of Tregs by M. tuberculosis required expression of programmed death1 (PD-1) and expression of the signaling molecule, cytokine inducible SH2-containing protein (CISH). Anti-PD-1 siRNA inhibited expression of CISH by expanded Tregs. M. tuberculosis-expanded Tregs produced transforming growth factor β and interleukin 10 and reduced the frequency of interferon γ-producing autologous CD8(+) cells. We conclude that M. tuberculosis infection induces development of Tregs from CCR4(+) cells through a process that depends on PD-1and CISH.
authors.affiliation: Center for Pulmonary and Infectious Disease Control, University of Texas Health Center, Tyler, India.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Periasamy
authors.forename: Rohan
authors.initials: R
authors.lastname: Dhiman
authors.forename: Peter F
authors.initials: PF
authors.lastname: Barnes
authors.forename: Padmaja
authors.initials: P
authors.lastname: Paidipally
authors.forename: Amy
authors.initials: A
authors.lastname: Tvinnereim
authors.forename: Anuradha
authors.initials: A
authors.lastname: Bandaru
authors.forename: Vijaya Lakshmi
authors.initials: VL
authors.lastname: Valluri
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Vankayalapati
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015704:CD4 Antigens / Q000032:analysis; D006801:Humans; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D054398:Receptors, CCR4 / Q000032:analysis; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens; D061026:Programmed Cell Death 1 Receptor; D054398:Receptors, CCR4; D050826:Suppressor of Cytokine Signaling Proteins; C515354:CCR4 protein, human; C105992:PDCD1 protein, human